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Treatment Name: RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side)

RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side) is a Chemotherapy Regimen for Lymphoma, B-cell

How does RICE (or R-ICE) chemotherapy work?
Each of the medications in the RICE chemotherapy regimen are designed to kill cancerous lymphocytes, a type of white blood cell. Rituixmab binds to the surface of the cancer cell, while ifosfamide, carboplatin, and etoposide all enter the cancer cell and attack its DNA.

R - Rituximab
I - Ifosfamide
C - Carboplatin
E - Etoposide

Goals of therapy:
RICE is given to shrink lymphoma and decrease symptoms related to lymphoma such as “B-Symptoms.” Once R-ICE chemo is complete, it is often followed by an autologous stem cell transplant (stems cells from yourself), and is commonly given with the goal of cure.

Schedule

Common Outpatient PLUS Inpatient/Hospital Schedule:

  • Infusion center: Rituximab intravenous (I.V.) infusion on Day 1. The time of infusion varies depending upon tolerability
  • Infusion center: Etoposide I.V. infusion over 1 hour on Day 1
  • In Hospital: Ifosfamide mixed with MESNA I.V. continuous infusion over 24 hours, beginning on Day 2 and ending on Day 3
  • In Hospital: Carboplatin I.V. infusion over 1 hour on Day 2 only
  • In Hospital: Etoposide I.V. infusion over 30 – 60 min on Days 2, and 3

Alternative Ambulatory Outpatient Schedule:

  • Rituximab intravenous I.V. infusion on Day 1, 8, 15, and 22 of cycle 1 only. The time of infusion varies depending upon tolerability
  • Ifosfamide mixed with MESNA I.V. infusion over 2 - 3 hours once daily on Days 1, 2, and 3
  • Carboplatin I.V. infusion over 1 hour on Day 2 only.
  • Etoposide I.V. infusion over 30 – 60 min on Days 1, 2, and 3
  • Oral Mesna (either mesna tablets or IV mesna diluted for oral administration) by mouth 2 hours after the ifosfamide dose AND 6 hours after the ifosfamide dose to prevent blood in the urine from acrolein build up

Note: the alternative ambulatory outpatient schedule of rice chemo may be MORE toxic to the bone marrow than the outpatient/inpatient regimen that uses continuous infusion ifosfamide as evidenced by lower neutrophil counts and lower platelet counts

Estimated total infusion time for this treatment:

  • Up to 8 hours for Cycle 1, Day 1; as short as 3 hours for the first day of next cycles if well tolerated
  • Infusion times are based on clinical studies, but may vary depending on doctor preference or patient tolerability. Pre-medications and intravenous (I.V.) fluids, such as hydration, may add more time

Day 1 of RICE chemotherapy is usually started in an outpatient infusion center, allowing the person to go home afterwards. Day 2 and 3 are usually completed in the hospital. On occasion, the entire cycle of RICE chemotherapy may be given in an infusion center if oral mesna is available, or the entire cycle of RICE chemotherapy many be given in the hospital if someone is too sick to go home.

RICE is repeated every 14 - 21 days, depending upon tolerability. This is known as one cycle. Each cycle may be repeated up to 4 times, depending upon the stage of the disease and availability of stem cells for transplant. Duration of therapy may last up to 4 months, depending upon response, tolerability, and number of cycles prescribed

Common RICE chemotherapy starting doses

Side Effects

In a multi-drug regimen, each medication has unique side effects. When these medicines are given together, drug-related side effects reported in clinical studies give the best estimate of what to expect. In clinical studies, often only the most severe side effects from RICE chemotherapy were reported and are shown here. Side effects sometimes have percentage ranges [example: 8 – 25%] because they differed between clinical studies:

Note: neutropenia from RICE chemo is usually brief, with the lowest neutrophil count usually occurring between day 7 and 11 after each new cycle

Side effect videos Side Effect Videos
BleedingBleedingNeutropenic FeverNeutropenic FeverBlood ClotsBlood ClotsNausea and VomitingNausea and VomitingHair LossHair LossAnemiaAnemiaFatigue Fatigue

Monitoring

How often is monitoring needed?
Labs (blood tests) may be checked before each treatment, if any signs of bleeding or infection, or as recommended by your doctor. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), LDH, Mg, Phos, and Uric acid, plus any others your doctor may order.

How often is imaging needed?
Imaging may be checked before treatment, 10 – 14 days after the third cycle, or as recommended by your doctor. Imaging may include: computerized tomography (CT scan) of the chest, abdomen, and pelvis, or positron emission tomography (PET scan) or both. A chest x-ray may be needed if an infection such as pneumonia is suspected during treatment.

How might blood test results/imaging affect treatment?
Depending upon the results, your doctor may advise to continue RICE chemo as planned, reduce the dose of future treatments, delay the next dose until the side effect goes away, or switch to an alternative therapy.

The dose of carboplatin may be adjusted depending upon how well the kidneys are working. This is usually determined by the serum creatinine (Scr), obtained from a CMP as described above.

If the platelet count or neutrophil count is too low on the day the next cycle of RICE chemotherapy is due, the cycle may be delayed by a few days to a week to allow for platelet recovery and reduce the risk of bleeding, the need for platelet transfusion, or the risk of infection.

ChemoExperts Tips

  • Because severe neutropenia and neutropenic fever are common after rice chemo, growth factor therapy known as G-CSF (examples: neupogen or neulasta) is recommended to help prevent this. G-CSF helps keep the good white blood cells, known as neutrophils, from dropping too low. This in turn, helps to prevent serious infections that could result in hospitalization or even death
  • Patients who plan to proceed with autologous stem cell transplant often collect stem cells after the third cycle of RICE using different doses of G-CSF than were used for cycles 1 and 2. Your transplant team will likely coordinate G-CSF dosing during stem cell collection
  • It is best to wash hands well throughout treatment, especially on days 7 – 11, while the neutrophil count is expected to be at its lowest point
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately
  • Mesna tablets are very expensive and not always covered by insurance plans (outpatient prescription (Rx) coverage plans). Your doctor should be able to have someone check ahead of time what the out-of-pocket cost is. Many pharmacies do NOT routinely carry MESNA tablets.
  • Clinical trials may exist for B-cell lymphoma. Ask your doctor if any studies are currently enrolling in your area. If not, go to clinicaltrials.gov to search for other centers offering study medications

Patient Assistance & Co-payment Coverage

Patients under the age of 65 years, or those with private insurance plans:
If you have insurance and are looking for patient assistance or copay assistance for RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side), we have provided links that may help.

Visit our Patient Assistance page and click the links to various patient assistance programs for help paying for RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side). Depending upon your income, they may be able to help cover the cost of:

  • Rituximab
  • Ifosfamide
  • Carboplatin
  • Etoposide

For Branded medications (may be available for generic medications too), check with the manufacturer to determine if a co-pay card is offered and if it could reduce your monthly copay.

  • If you are uninsured, check with the manufacturer to determine if you are eligible to receive medication at no cost.

Medicare and Medicaid patients (Patients 65 years or older):
The clinic providing treatment will likely pre-authorize medications and immune therapies such as RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side) and are the best source to help you understand drug cost.

  • Ask to speak with a patient assistance technician or financial counselor at the clinic or hospital administering this therapy.

Emotional Wellness

What is Emotional Wellness?
Emotional wellness is having a positive outlook balanced with a realistic understanding of current life events. This requires both an awareness and acceptance of your emotions. It is with this knowledge that you can develop a plan to take the necessary actions to positively impact your life.

Emotional wellness uses an ongoing process to continually reflect on the stressors of life in a constructive manner to move forward and create happiness.

Because emotional wellness is deeply connected with physical, social, and spiritual wellness, pursuing it often becomes particularly difficult in times of major illness. Despite this difficulty, working toward emotional wellness has been connected to improved treatment outcomes and a higher likelihood of achieving goals of therapy.

Learn more about pursuing emotional wellness while receiving treatment with RICE (Rituximab + Ifos­famide + Carbo­platin + Etopo­side)

Individual Drug Label Information

Rituximab (Rituxan®)

  • Rituximab is an intravenous infusion
  • Acetaminophen (Tylenol®) and antihistamines (e.g. diphenhydramine = Benadryl®) should be given prior to each dosePatients should be screened for hepatitis B as rituximab can cause a re-activation of this infection
  • May cause vaccines to work less well. It is advised that vaccines be given two to four weeks prior to rituximab if possible
General Rituximab (Rituxan) Side Effects
  • May cause an infusion reaction, which could include skin reaction, shaking, chills, fever, or shortness of breath. These reactions may be severe, but are very rarely life-threatening
  • Infusion reactions does not usually happen after the first dose, but are possible
  • May increase the risk of infection. Your doctor may prescribe antibiotics to prevent certain infections associated with rituximab use
  • Click on the rituximab (Rituxan) package insert below for reported side effects and potential drug Interactions
See DailyMed package insert.

Ifosfamide (Ifex®)

  • Ifosfamide is an intravenous (I.V.) infusion
  • Has been linked to the development of other cancers in a small number of people 
  • Your blood counts will be monitored closely while on therapy and your chemotherapy may need to be delayed due to low red blood cells, white blood cells, and platelets
  • Symptoms of neurotoxicity from ifosfamide include tiredness, confusion, dizziness, mood changes, hallucinations, seizure, and coma. You will be checked for any signs of neurotoxicity prior to receiving each dose of ifosfamide. If these occur during treatment, ifosfamide infusion should be interrupted until the symptoms go away
  • Bladder irritation may occur and result in blood in the urine. This may appear as pink urine, or bright red, depending upon how much blood is being lost. Drink plenty of fluids (1-2 liters/day), especially during the days when ifosfamide is given. Frequent urination will also help flush the bladder and avoid bladder irritation
  • Your kidney function will be monitored while on therapy with ifosfamide. Dosage adjustments may be required for decreased kidney function
  • A smaller dosage may be required for patients receiving hemodialysis
  • May decrease the ability to become pregnant. Fertility preservation is recommended in couples wishing to become pregnant
  • Has been linked to the development of other cancers in a small number of people
General Ifosfamide (Ifex) Side Effects 
  • Can cause lung toxicity leading to decreased lung function
  • Commonly causes hair loss, which is usually reversible
  • Has been linked to the development of other cancers in a small number of people
  • Low white blood cell count which can increase the risk of infection
  • Nausea or vomiting, which can be acute (first 24 hours) or delayed (Days 2 – 5)
  • Click on the Ifosfamide (Ifex) package insert below for reported side effects and possible drug iteractions

Side Effect Videos
DiarrheaDiarrheaHair LossHair LossFatigue Fatigue PainPainAnemiaAnemiaNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

Carboplatin (Paraplatin®)

  • Carboplatin is an intravenous infusion 
  • This medication is dosed based on your kidney function. If your kidney function improves or worsens during therapy, your dose may need to be adjusted
  • This drug should not be used during pregnancy, it may cause fetal harm
General Carboplatin (Paraplatin) Side Effects:  
  • Low red blood cells, low white blood cells, and most commonly, low platelets can be occur
  • Nausea and vomiting is common but can be prevented by taking certain pre-medications
  • Hair loss
  • Constipation and/or diarrhea
  • Pain
  • Allergic reactions to carboplatin can occur. These typically are not seen until after the 6th dose of carboplatin is given 
  • Can cause liver damage at high doses 
  • May cause kidney damage or hearing loss if combined with other medications that also cause these side effects 
  • Click on the carboplatin (Paraplatin) package insert below for reported side effects and possible drug interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaHair LossHair LossBleedingBleedingConstipationConstipationPainPainAnemiaAnemia

See DailyMed package insert.

Etoposide (VP-16)

  • Etoposide is an intravenous (I.V.) infusion that is typically given over 30-60 minutes or in some instances, as a continuous infusion
  • Etoposide interacts with grapefruit juice and can cause increased exposure to etoposide if taken together
  • Dosage adjustments may be required for decreased kidney or liver function
General Etoposide (VP-16) Side Effects
  • Often causes temporary hair loss, which is usually reversible after stopping etoposide therapy
  • Gastrointestinal side effects such as diarrhea, mouth sores, nausea and upset stomach can be common
  • Although rare, it has been linked to the development of acute leukemia (2-12%) and typically occurs 2-3 years after therapy
  • May cause low blood counts (white blood cells, red blood cells, and platelets)
  • Click on the etoposide (VP-16) package insert below for reported side effects and potential drug Interactions

Side Effect Videos
DiarrheaDiarrheaHair LossHair LossFatigue Fatigue BleedingBleedingAnemiaAnemiaNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

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References

1) Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-4190.

2) Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684-3688.

3) Hertzberg MS, Crombie C, Benson W, et al. Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma. Ann Oncol. 2006;17(Suppl 4):iv25-iv30.

Created: February 18, 2017 Updated: February 18, 2017

What is Lymphoma, B-cell?

B-cell Lymphoma is a disease of the white blood cells known as B-lymphocytes which are normally found in lymph nodes, blood, and throughout the body. There are many different types of lymphoma, most of which are rare. Known causes of lymphoma may include immunosuppressive medications, infections such as HIV, while some causes are still unknown. The stage of lymphoma can vary at diagnosis and throughout treatment. The effectiveness of the treatment may depend upon the sub-type of lymphoma and stage at diagnosis.

NOTE: Treatment Options listed below are not all-inclusive. Other treatments may be available. ChemoExperts provides drug information and does not recommend any one treatment over another. Only your Doctor can choose which therapy is appropriate for you.

What are “B-Symptoms”?

a. Fever – a temperature greater than 100.5° F
b. Night Sweats – usually drenching night sweats, often requiring a change of bed sheets or pajamas
c. Weight Loss – Unintentional weight loss of more than 10% body weight in the 6 month period before diagnosis

What does "Cure" mean?

The word “cure” means there are no cancer cells left in the body and cancer will never come back. Depending on the cancer type and stage, this may be the true goal of therapy. However, it is very difficult to prove all cancer cells are gone. Even though images, like X-rays and MRI’s, and blood tests may not show any signs of cancer, there can be a small amount of cancer cells still left in the body. Because of this, doctors use the word “remission” is used more often. This means there are no signs or symptoms of cancer. Patients in remission are followed closely for any signs of cancer returning. Sometimes, more chemotherapy may be given while in remission to prevent the cancer from coming back.

Doctors usually do not consider a patient “cured” until the chance of cancer returning is extremely low. If cancer does return, it usually happens within 5 years of having a remission. Because of this, doctors do not consider a patient cured unless the cancer has not come back within 5 years of remission. The five-year cutoff does not apply to all cancers.

What is MESNA?

Mesna is not a chemotherapy agent. It binds to and neutralizes a toxic metabolite of ifosfamide known as acrolein. It is an acronym which stands for: MercaptoEthane Sulfonate sodium (sodium is abbreviated as Na).

What are mesna tablets?

MESNA is usually given intravenously. On occasion, MESNA is prescribed as oral tablets. Mesna tablets do not taste good and can make a nauseated patient feel worse. If a patient vomits within two hours of taking oral mesna, they should contact their doctor to see if another dose is needed

What is "I.V. mesna diluted for oral administration"?

I.V. mesna is sometimes diluted with water and given by mouth as an alternative to the tablets. The reason is that the I.V. mensa vials are often less expensive than oral tablets. If mesna tablets are too expensive, talk to your doctor or pharmacist about possibly using the I.V. form of mesna diluted and taken by mouth to save money.

What is acrolein?

Acrolein is a breakdown product (metabolite) of ifosfamide. If too much acrolein builds up in the bladder, it harms the cells lining the bladder and causes bleeding. Mesna helps lessen the risk of this side effect by binding to and neutralizing acrolein. MESNA is very effective at preventing bleeding from the bladder.

Common RICE chemotherapy starting doses

Common Outpatient PLUS Inpatient/Hospital Schedule:

  • Infusion center: Rituximab 375 mg/m2 intravenous (I.V.) infusion on Day 1. The time of infusion varies depending upon tolerability
  • Infusion center: Etoposide 100 mg/m2 intravenous infusion over 1 hour on Day 1
  • Hospital: Ifosfamide 5000 mg/m2 mixed with MESNA 5000 mg/m2 I.V. continuous infusion over 24 hours, beginning on Day 2 and ending on Day 3
  • Hospital: Carboplatin (area under the curve [AUC] 5; max dose 800 mg) I.V. infusion over 1 hour on Day 2 only. Carboplatin dose = 5 x [25 + CLcr], capped at 800 mg max dose.
  • Hospital: Etoposide 100 mg/m2 intravenous infusion over 30 – 60 min on Days 2, and 3

Alternative Ambulatory Outpatient Schedule:

  • Rituximab 375 mg/m2 intravenous (I.V.) infusion on Day 1, 8, 15, and 22 of cycle 1 only. The time of infusion varies depending upon tolerability
  • Ifosfamide 1667 mg/m2 mixed with MESNA 1667 mg/m2 I.V. infusion over 2 - 3 hours once daily on Days 1, 2, and 3 (total ifosfamide and MESNA doses = 5000 mg/m2 each per cycle)
  • Carboplatin (area under the curve [AUC] 5; max dose 800 mg) I.V. infusion over 1 hour on Day 2 only. Carboplatin dose = 5 x [25 + CLcr], capped at 800 mg max dose.
  • Etoposide 100 mg/m2 I.V. infusion over 30 – 60 min on Days 1, 2, and 3
  • Oral Mesna 2000 mg (either mesna tablets or IV mesna diluted for oral administration) by mouth 2 hours after the ifosfamide dose AND 6 hours after the ifosfamide dose to prevent blood in the urine from acrolein build up

Clinical Studies

If you are interested in reading the clinical trials results, please click on references below:

1) Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-4190.

2) Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684-3688.

3) Hertzberg MS, Crombie C, Benson W, et al. Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma. Ann Oncol. 2006;17(Suppl 4):iv25-iv30.

What is a CBC?

A Complete Blood Count (CBC) is a frequently ordered blood test that tells clinicians the status of your: 1) White blood cell count, 2) Hemoglobin, and 3) Platelet count at the time the test was taken.

Common uses:
1) White blood cell count (WBC): is used to determine infection risk, or response to chemotherapy. Certain chemotherapy agents may harm our good infection-fighting cells. Sometimes chemotherapy may need to be delayed to allow these cells to recover.

2) Hemoglobin: is used to determine if someone is anemic. Anytime the hemoglobin is below 12 g/dL, the person is said to be anemic. Red blood cell transfusions, and sometimes iron can be given to restore the hemoglobin level, but anemia treatment should always aim at treating the underlying cause or condition.

3) Platelet count: is used to determine if the risk of bleeding is increased or if a platelet transfusion is required to prevent bleeding. Certain medications that increase bleeding risk, such as: aspirin, certain chemotherapy agents, and blood thinners, may need to be stopped temporarily until the platelet count is within a safe range.

What is a CMP?

A Comprehensive Metabolic Panel (CMP) is a frequently ordered blood test that tells clinicians the status of your: 1) Electrolytes & Acid/Base status2) Kidney function, 3) Liver function, 4) Blood sugar, and 5) Calcium at the time the test was taken. It is commonly used to monitor liver and kidney function when beginning new medications such as chemotherapy. A total of 14 tests are run simultaneously and are shown below.

Electrolytes & Acid/Base status:
1) Sodium, 2) Potassium, 3) Carbon dioxide, 4) Chloride

Kidney Function:
5) BUN (blood urea nitrogen), 6) Serum creatinine (Scr)

Liver Function:
7) AST, 8) ALT, 9) Total bilirubin, 10) Alk Phos, 11) Albumin, 12) Total protein

Blood sugar:
13) Serum glucose

Calcium:
14) Serum calcium